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Hexokinase
''' Hexokinase is a transferase protein. It is the first enzyme in the glycolytic pathway that converts glucose into glucose-6-phosphate. This enzyme uses ATP to phosphorylate the 6-hydroxyl group of glucose, which is inhibited by its product, glucose-6-phosphate. It is also allosterically relieved of product inhibition by the addition of phosphate. Hexokinase controls the flow of glucose into energy metabolism in many mammalian tissues, such as blood cells, and brain tissue. Glucose-6-phosphate and glucose bind synergistically to hexokinase, as well as glucose and phosphate. This phosphate however plays a small role in the regulation of hexokinase during respiration. This is because gylcolysis is limited by the supply of glucose. During times of oxygen deprivation more ATP must come from glycolysis. This occurs because pyruvate forms lactic acid instead of entering the Kerb's cycle. As ATP phosphorylates glucose to glucose-6-phosphate, it increases its Gibbs free energy from -31 KJ to 14.3 KJ. This makes the reaction thermodynamically favorable.

Reaction
During the first step of glycolysis, the gama-phosphoryl group of an ATP molecule is transferred to the oxygen at the C-6 position of glucose. A magnesium ion is required because the reactive form of ATP is the chelated complex with magnesium (II) ion. This is a direct nucleophillic attack of the hydroxyl group on the terminal phosphoryl group of ATP molecule. This reaction produces glucoe-6-phosphate, and ADP.



Structure
The structure of hexokinase was first determined from yeast by Tom Steitz at Yale University. This compound is composed of a large homodimer of 920 amino acids in each chain. Each chain is about equal molecular weights. Hexokinase has a tertiary structure which includes an open alpha/beta sheet. There is a lot of variation associated with this structure. It’s composed of three alpha helices, and five beta sheets. The open beta sheet is composed of four parallel sheets, and one antiparallel sheet. The beta loops connect the alpha helices and beta sheets to produce this open alpha/beta sheet. Hexokinase is capable of binding two ligands, glucose, and glucose-6-phosphate.

Active Sites The active site residues for Hexokinase are Asp205, Lys169, Asn204, Glu256,and Thr168. These residues are located in the deep cleft at the interface between the two lobes. This active site is capable of bonding two ligands, glucose, and glucose-6-phosphate. Hexokinase undergoes an induced fit conformational change when glucose binds. This conformational change prevents the hydrolysis of ATP, and is allosterically inhibited by physiological concentrations of glucose-6-phosphate the product. Hexokinase has two conformational states. The open state occurs prior to glucose binding. ATP is bound to the large lobe, but is far away from the glucose binding site, and in a different position than it assumes in the active site. When the glucose binds to Hexokinase a large conformational change occurs. This change closes the two lobes around the glucose substrate. This conformational state is referred to as the closed state.

The active site residues in the open conformational structure for hexokinase are far away from the ligand binding site. Active Sites (GREEN)Ligands(YELLOW)